Oral cavity squamous cell carcinoma (OSCC) is the most common oral malignancy, and is increasing in incidence. Bone invasion by OSCC correlates with recurrence and worsened disease-specific survival. OSCC invades adjacent bone by direct extension rather than by metastasis, and previous studies indicated that this invasion is osteoclast-mediated. The mechanisms of bone invasion of OSCC are only partially understood. The purpose of this project is to elucidate osteoactivin's role in OSCC bone invasion. Osteoactivin (OA) was first identified as a gene differentially expressed in melanoma cells with high and low metastatic potentials. OA is known to play a role in invasion, including bone invasion, and metastasis in several malignancies including breast carcinomas, malignant melanoma, and squamous cell lung carcinoma. Moreover, OA promotes osteoclast differentiation and angiogenesis. Our preliminary data indicate that OA is expressed in OSCC cells and promotes tumor cell migration. Tumor-stromal interactions have been shown to promote aggressive behavior in OSCC. We will determine whether OA plays a role in invasion and tumor-induced osteoclast differentiation in OSCC. In Aim 1 of this project, we will determine if OA promotes OSCC cell migration, and tumor-mediated osteoclastogenesis. Suppression of OA expression in the OSCC cells will be used to confirm OA's effects on tumor invasion, and osteoclast differentiation and activation. In Aim 2, we will use an animal model of OSCC bone invasion to assess OA's role in osteoclast-mediated tumor bone invasion. This work will expand our understanding of bone invasion by OSCC, and may identify OA is a marker of bone invasion and a potential therapeutic target in OSCC treatment.